DESCRIPTION: Bladder cancer is the third most prevalent cancer among men in th USA. Superficial transitional cell carcinomas (TCCs) account for 80-90% of bladder cancers. These TCCs are often multifocal, but are usually not life-threatening. However, ~60% of patients with multiple tumors have recurrences within 4 years, and ~25% of recurrent tumors progress to muscle invasive cancer. An estimated one third of such patients die of bladder cancer in 15-year follow-up studies. Mortality could be reduced if marker(s) were available to predict which superficial TCCs are at highest risk for progression. Unfortunately, the biological significance of genetic alterations in TCCs relative to progression have not been defined. The objective of this proposal is to test a new model for TCC progression. Previous models have focused on p53 alteration as the critical event in progression. New findings suggest that the use of a single genetic marker to predict tumor phenotype is inadequate, rather a phenotype that might require several markers should be evaluated. The research group will test the hypothesis that overcoming the tumor suppressor mechanism of cellular senescence is critical to progression. They will also show that bypassing senescence can be accomplished by several combinations of different genetic alterations. The Specific Aims to fulfill these goals are: (1) to identify genetic alterations in superficial TCCs and (in a retrospective study) to determine if any genotype present in superficial TCCs has value for predicting progression on recurrence; (2) to determine if superficial TCCs when they progress to muscle invasive TCCs have bypassed senescence; and finally (3) to test if altering p16-mediated senescence growth block by genetic manipulation completes requirements for bypassing senescence in superficial TCCs. The proposed studies are significant because they will lead to a better understanding of bladder cancer pathogenesis. They are also clinically relevant because they may identify useful prognostic markers for TCC.